Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, play a major role in migration, retention, and development of hematopoietic progenitors in the bone marrow. We report the direct involvement of atypical PKC-zeta in SDF-1 signaling in immature human CD34(+)-enriched cells and in leukemic pre-B acute lymphocytic leukemia (ALL) G2 cells. Chemotaxis, cell polarization, and adhesion of CD34(+) cells to bone marrow stromal cells were found to be PKC-zeta dependent. Overexpression of PKC-zeta in G2 and U937 cells led to increased directional motility to SDF-1. Interestingly, impaired SDF-1-induced migration of the pre-B ALL cell line B1 correlated with reduced PKC-zeta expression. SDF-1 triggered PKC-zeta phosphorylation, translocation to the plasma membrane, and kinase activity. Furthermore we identified PI3K as an activator of PKC-zeta, and Pyk-2 and ERK1/2 as downstream targets of PKC-zeta. SDF-1-induced proliferation and MMP-9 secretion also required PKC-zeta activation. Finally, we showed that in vivo engraftment, but not homing, of human CD34(+)-enriched cells to the bone marrow of NOD/SCID mice was PKC-zeta dependent and that injection of mice with inhibitory PKC-zeta pseudosubstrate peptides resulted in mobilization of murine progenitors. Our results demonstrate a central role for PKC-zeta in SDF-1-dependent regulation of hematopoietic stem and progenitor cell motility and development.
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PMID:Atypical PKC-zeta regulates SDF-1-mediated migration and development of human CD34+ progenitor cells. 1563 Apr 39

Dendritic cells (DC) arise from a diverse group of hematopoietic progenitors and have marked phenotypic and functional heterogeneity. The signal transduction pathways that regulate the ability of progenitors to undergo DC differentiation, as well as the specific characteristics of the resulting DC, are only beginning to be characterized. We have found previously that activation of protein kinase C (PKC) by cytokines or phorbol esters drives normal human CD34(+) hematopoietic progenitors and myeloid leukemic blasts (KG1, K562 cell lines, and primary patient blasts) to differentiate into DC. We now report that PKC activation is also required for cytokine-driven DC differentiation from monocytes. Of the cPKC isoforms, only PKC-betaII was consistently activated by DC differentiation-inducing stimuli in normal and leukemic progenitors. Transfection of PKC-betaII into the differentiation-resistant KG1a subline restored the ability to undergo DC differentiation in a signal strength-dependent fashion as follows: 1) by development of characteristic morphology; 2) the up-regulation of DC surface markers; 3) the induction of expression of the NFkappaB family member Rel B; and 4) the potent ability to stimulate allo-T cells. Most unexpectedly, the restoration of PKC-betaII signaling in KG1a was not directly due to overexpression of the transfected classical PKC (alpha, betaII, or gamma) but rather through induction of endogenous PKC-beta gene expression by the transfected classical PKC. The mechanism of this positive autoregulation involves up-regulation of PKC-beta promoter activity by constitutive PKC signaling. These findings indicate that the regulation of PKC-betaII expression and signaling play critical roles in mediating progenitor to DC differentiation.
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PMID:Protein kinase C betaII plays an essential role in dendritic cell differentiation and autoregulates its own expression. 1591 49

The management of cancer involves procedures, which include surgery, radiotherapy and chemotherapy. Development of chemoresistance is a persistent problem during the treatment of local and disseminated disease. A plethora of cytotoxic drugs that selectively, but not exclusively, target actively proliferating cells include such diverse groups as DNA alkylating agents, antimetabolites, intercalating agents and mitotic inhibitors. Resistance constitutes a lack of response to drug-induced tumour growth inhibition; it may be inherent in a subpopulation of heterogeneous cancer cells or be acquired as a cellular response to drug exposure. Resistance varies. Although regulatory approval may require efficacy in as few as 20% of trial cohorts, a drug may subsequently be used in unselected patients displaying resistance to the treatment. Principal mechanisms may include altered membrane transport involving the P-glycoprotein product of the multidrug resistance (MDR) gene as well as other associated proteins, altered target enzyme (e.g. mutated topoisomerase II), decreased drug activation, increased drug degradation due to altered expression of drug-metabolising enzymes, drug inactivation due to conjugation with increased glutathione, subcellular redistribution, drug interaction, enhanced DNA repair and failure to apoptose as a result of mutated cell cycle proteins such as p53. Attempts to overcome resistance mainly involve the use of combination drug therapy using different classes of drugs with minimally overlapping toxicities to allow maximal dosages and with narrowest cycle intervals, necessary for bone marrow recovery. Adjuvant therapy with P-glycoprotein inhibitors and, in specific instances, the use of growth factor and protein kinase C inhibitors are newer experimental approaches that may also prove effective in abrogating or delaying onset of resistance. Gene knockout using antisense molecules may be another effective way of blocking drug resistance genes. Conversely, drug resistance may also be used to good purpose by transplanting retrovirally transformed CD34 cells expressing the MDR gene to protect the bone marrow during high-dose chemotherapy.
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PMID:Mechanisms of drug resistance in cancer chemotherapy. 1610 12

Apoptosis plays a central role in the regulation of the size of the hematopoietic stem cell pool as well as in the processes of cell differentiation along the various hematopoietic lineages. TRAIL is a member of the TNF family of cytokines with a known apoptogenic role against a variety of malignant cells and an emerging role in the modulation of normal hematopoiesis. Here we worked on the hypothesis that PKCepsilon could act as a switch of the cellular response to TRAIL during erythropoiesis. We demonstrate that EPO-induced erythroid CD34 cells are insensitive to the apoptogenic effect of TRAIL at day 0 due to the lack of specific receptor expression. From day 3 onward, erythroid cells express surface death receptors and become sensitive to TRAIL up to day 7/8 when, notwithstanding death-receptor expression, the EPO-driven up-regulation of PKCepsilon intracellular levels renders differentiating erythroid cells resistant to TRAIL likely via Bcl-2 up-regulation. Our conclusion is that in human CD34 cells, EPO promotes a series of events that, being finely regulated in their kinetics, restricts the sensitivity of these cells to TRAIL to a specific period of time, which therefore represents the "TRAIL window" for the negative regulation of erythroid-cell numbers.
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PMID:PKCepsilon controls protection against TRAIL in erythroid progenitors. 1616 86

CD163, the hemoglobin-haptoglobin receptor, has been reported to be expressed exclusively on monocyte/ macrophages. Here we demonstrate that CD163 is also expressed by a subpopulation of hematopoietic stem/progenitor cells. Flow cytometric analysis shows that 1.9 +/- 1.3% (+/-SD, n = 16) of adult bone marrow and 2.0 +/- 1.8% (n = 8) of umbilical cord blood CD34(+) cells express cell-surface CD163, and 69.1 +/- 16.9% (n = 9) and 79.7 +/- 22.4% (n = 8) of the respective cells contain the CD163 protein intracellularly. The expression of CD163 by CD34(+) cells was confirmed by western blot analysis of cell lysates. Transcripts corresponding to the known predominant and variant 1 forms of CD163 were amplified via RT-PCR from CD34(+) cell-derived mRNA. A new variant (K11) with a deletion at the start of exon 15 was also detected. The deleted region contains a PKCalpha phosphorylation site and an amino acid sequence (YREM) that may support efficient receptor endocytosis. The addition of activating anti-CD163 antibodies increased the growth and differentiation of erythroid progenitors in colony-forming assays. These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells.
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PMID:Expression of the hemoglobin-haptoglobin receptor CD163 on hematopoietic progenitors. 1652 61

The regulation of the hematopoietic stem cell pool size and the processes of cell differentiation along the hematopoietic lineages involve apoptosis. Among the different factors with a recognized activity on blood progenitor cells, TRAIL - a member of the TNF family of cytokines - has an emerging role in the modulation of normal hematopoiesis.PKC(epsilon) levels are regulated by EPO in differentiating erythroid progenitors and control the protection against the apoptogenic effect of TRAIL. EPO-induced erythroid CD34 cells are insensitive to the apoptogenic effect of TRAIL between day 0 and day 3, due to the lack of specific surface receptors expression. Death receptors appear after day 3 of differentiation and consequently erythroid cells become sensitive to TRAIL up to day 9/10, when the EPO-driven up-regulation of PKC epsilon intracellular levels inhibits the TRAIL-mediated apoptosis, via Bcl-2. In the time interval between day 3 and 9, therefore, the number of erythroid progenitors can be limited by the presence of soluble or membrane-bound TRAIL present in the bone marrow microenvironment.
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PMID:TNF-related apoptosis-inducing ligand (TRAIL) and erythropoiesis: a role for PKC epsilon. 1658 80

Penile malignancies are rare in developed countries. The authors present a case of a penile urethral mesenchymal tumor occurring in a 51-year-old Caucasian male and displaying light microscopic, immunohistochemical, and ultrastructural features suggestive of a pacemaker cell type, combined with a lack of diagnostic features of any other established tumor category. The immunohistochemical profile was intensely positive for vimentin, PKC theta, and NSE and weakly positive to nonreactive for CD34 and smooth muscle actin, and entirely negative for CD117 (c-kit), S-100, and other markers. C-kit and PDGFRA gene analysis showed no mutations. Electron microscopy revealed tumor cells with plentiful cytoplasm and cytoplasmic processes/filopodia, both filled with intermediate filaments and occasional solitary focal densities. There were also prominent smooth endoplasmic reticulum cisternae, caveolae, neurosecretory granules, particularly concentrated in cytoplasmic processes, and synaptic-type structures. Poorly formed basal lamina, gap junctions, and intercellular collagen aggregates, consistent with skeinoid-type fibers, were also noted. Interstitial cells with potential pacemaker function have been recently described in the lower urinary tract, including the urethra, and this tumor may be related to this cellular phenotype.
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PMID:Urethral stromal tumor with pacemaker cell phenotype. 1745 99

Global gene expression analysis established the temporal expression patterns and programs underlying the development of functional activity of ex vivo-expanded (EXE) human granulocytes, as well as differences compared with peripheral blood (PB) granulocytes. CD34(+) progenitor cells were cultured for 3 wk to induce rapid expansion and granulocytic differentiation, with 40% CD15(+) cells by day 3 and 90% by day 12. Phagocytic and respiratory burst activity increased with the fraction of CD15(++)CD11b(+) cells (myelocytes to segmented) and peaked by day 17. However, only 25% of CD15(++)CD11b(+) cells were phagocytic, and respiratory burst activity was one-third that of PB granulocytes. EXE granulocytes from later days and PB granulocytes showed similar expression of Fc gamma receptors (-1A, -2A, -2C, -3A) and complement receptors (-1, -3, -4). Later downregulation of CD36 (expressed by macrophages) suggests lineage plasticity early in granulocytic differentiation. Expression in mature EXE and PB granulocytes was similar for most Fc gamma receptor-mediated phagocytosis signaling proteins, including high-level expression of Hck, Fgr, and the actin-related protein 2/3 complex. Lower expression of Lyn, Cdc42, pleckstrin, and PKC beta(I) by EXE granulocytes may explain decreased phagocytosis. PB and mature EXE granulocytes expressed similar levels of NADPH oxidase complex genes and receptors for fMLP-mediated respiratory burst. Lower burst activity by EXE granulocytes may result from lower expression of Raf1 and PKC zeta. Elevated expression of toll-like receptor (TLR)2, TLR1, and CD14 in mature EXE and PB granulocytes supports a role for the TLR2 and CD14 pathway in zymosan-mediated respiratory burst activity. Lower activity in EXE granulocytes may be due to greater expression of IRAK3, which inhibits TLR-mediated signaling.
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PMID:Gene expression analysis illuminates the transcriptional programs underlying the functional activity of ex vivo-expanded granulocytes. 1755 Sep 95

Protein kinase C (PKC)-mediated intracellular signaling participates in several key steps of hematopoietic cell differentiation. The epsilon isoform of PKC has been associated with erythroid differentiation as well as with the early phases of megakaryocytic (MK) lineage commitment. Here, we worked on the hypothesis that PKCepsilon expression levels might be modulated during MK differentiation, with a specific role in the early as well as in the late phases of thrombopoiesis. We demonstrate that--at variance with the erythroid lineage development--PKCepsilon is completely downmodulated in TPO-induced CD34 cells from day 6 onward. The forced expression of PKCepsilon in the late phases of MK differentiation delays the phenotypic differentiation of progenitors likely via Bcl-xL upregulation. Moreover, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), known as a negative regulator of early erythroid expansion, is not apoptogenic for thrombopoietin-induced CD34 cells, but rather accelerates their maturation. However, PKCepsilon levels negatively interfere also with the effects of TRAIL in MK differentiation. PKCepsilon can therefore be considered a signaling intermediate whose expression levels are finely tuned, with a virtually opposite kinetic, in erythroid versus megakaryocytic lineages, to adequately respond to the signaling requirements of the specific hematopoietic lineage.
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PMID:Timing and expression level of protein kinase C epsilon regulate the megakaryocytic differentiation of human CD34 cells. 1756 88

In order to study the role of the cytokine interleukin-3 (IL-3) and its signaling pathways in erythropoiesis of beta-thalassemia/HbE erythroid progenitor cells, CD34 positive cells were isolated from peripheral blood of patients and healthy subjects. After culturing the cells in the presence or absence of IL-3, cell viability was measured by trypan blue staining and apoptotic cells were analyzed by flow cytometry. After 7 days of culture the highest percent erythroid progenitor cell viability was obtained with cells from healthy subjects, while the lowest percentage was found in those from splenectomized beta-thalassemia/HbE. Viability of beta-thalassemia/HbE erythroid progenitor cells in the presence of IL-3 was higher than that of nonsupplemented cells. In addition, specific inhibitors of protein kinase C (Ro-318220), phospholipase C (U-73122) and Janus kinase 2 (AG-490) were used to investigate the involvement of signaling pathways in erythropoiesis. Percent apoptosis of erythroid progenitor cells from splenectomized beta-thalassemia/HbE subjects treated with RO-318220 was higher than those of nonsplenectomized beta-thalassemia/HbE and healthy subjects. Treatment with U-73122 resulted in enhanced percent apoptotic cells from normal and beta-thalassemia/HbE subjects. All these effects were independent of IL-3 treatment.
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PMID:Role of interleukin-3 and signaling pathways on beta-thalassemia/HbE erythroid progenitor cell in culture. 1804 9


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